This is a divisional application U.S. application Ser. No. 11/883,331. Benefit of this nonprovisional application is hereby claimed in accordance with 35 USC 121.
Diclofenac is used, most commonly, as the sodium or Potassium salt for relief from pain and inflammation such as Musculoskeletal and joint disorders including rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. It is also useful in peri-articular disorders such as renal colic, acute gout, dysmenorrheal following surgical procedures. It has also been used in some countries for the management of fever.
British National Formulary recommends intramuscular injection into the gluteal muscle. Likewise, Martindale, the Extrapharmacopoea recommends intragluteal injections. The other route of administration, recommended is by IV infusion.
A typical parenteral administration is prepared by suspending or dissolving Sodium/Potassium salt of diclofenac in a non-toxic aqueous or oleaginous medium liquid vehicle.
Diclofenac injections have to be administered deep intramuscularly and are generally administered intraguluteally as the injection causes substantial pain at the site of injection and its administration in the deltoid (upper arm) region is generally avoided.
Pain at the site of injection is due to relatively large volume of the injection (3 mL) and the fact that the injection solution contains relatively high volumes of propylene glycol, which is a known irritant upon parenteral administration. As mentioned in Applied Nursing Research, Vol. 16, No. 2, August, 2002 empirical data from published research reports, recommendations of established advisory panels and generally accepted scientific principals conclude that only small volumes of medication (2 ml or less) should be given in the deltoid site. In fact, according to Nursing, January 1997, page 62-63, recommends the use of deltoid muscle only for volumes of 1 mL or less.
On the other hand intramuscular injection volumes above 2 ml and up to 5 ml must be administered into the gluteal muscle (Applied Nursing Research, Vol. 16, No. 2, August, 2002). This is because; the gluteal muscle is larger as compared to the deltoid muscle and hence can accommodate the relatively larger injected volume (3-5 ml). On the other hand if this relatively larger volume is injected into the deltoid muscle, which has relatively lesser muscle mass, the injected solution will cause excessive stretching of the muscle fiber, thereby damaging the local muscle tissue and hence cause pain and discomfort to the patient. (Svendsen and Blom, Arch. Toxicol, Suppl. 7, 1984)
Further, injectable diclofenac preparations contain relatively high amounts (18-40%) of propylene glycol, which is a known irritant. The Extra pharmacopoeia 28th edition, Hand book of excipients, further reports that aqueous solution of 2% propylene glycol iso-osmotic with serum causes 100% haemolysis of erythrocytes in 45 min. (Martindale, the Extrapharmacopoea 28th Edition).
Formulators have attempted to eliminate propylene glycol from the formulation in order to minimize pain at the site of the injection. It must be however be appreciated that the total volume of the injection solution plays a very significant role in addition to the amount of propylene glycol in the cause of pain at the site of the injection. As mentioned above, the volume of the injected solution causes stretching of the muscle fiber, and the higher the volume, more is the damage to the local muscle tissue and hence pain and discomfort at the site of injection.
U.S. Pat. No. 3,558,690 discloses injectable preparations comprising water soluble salts of substituted phenyl acetic acid derivatives (diclofenac being one such compound) in concentrations of 0.5 to 5%
Conventional diclofenac injections marketed as single dose ampoules, contain 75 mg diclofenac sodium in 3 mL aqueous solution (2.5%). Multi dose vials (30 mL) contain 750 mg in 30 mL solution (10 doses) are also being marketed.
PCT application number WO 9603121 A1 describes a antiphlogistic, analgesic, antipyretic parenteral preparation comprising diclofenac, its salt, or both, a surfactant, co-surfactant, water, at pH of 3-10 and optionally comprising an only component, that can exhibit sustained therapeutic levels of diclofenac in plasma and which does not cause pain at site of injection.
U.S. Pat. No. 5,554,650 discloses an antiphlogistic, analgesic, antipyretic parenteral preparation that can exhibit sustained therapeutic levels of diclofenac in plasma comprising diclofenac, its salt, or both, a surfactant, co-surfactant, water, adjusted to pH of 3-10 and optionally comprising an oily component. Some preparations claim not to cause pain at site of injection since they exclude propylene glycol and instead use a surfactant and co-surfactant or oil with surfactant and co surfactant to dissolve the diclofenac.
European Patent Application number 0658347 A3 describes a method of preparing an injectable pharmaceutical or veterinary composition, which comprises either diclofenac or a salt thereof, and 2 hydroxypropyl betacyclodextrin, or an inclusion complex of diclofenac or a salt thereof and 2 hydorxypropyle betacyclodextrin. Propylene glycol is excluded and solubilisation effected with the help of 2 hydroxypropyl betacyclodextrin.
The present inventions attempts to provide preparations of concentrated solutions of water soluble salts of diclofenac and reducing the overall volume of injection to 1 mL resulting in the minimization of pain at site of injection. Further, smaller volume enables administration in the deltoid muscle.
While incorporating 75-100 mg of water-soluble salts of diclofenac and reducing the volume of the injection solution from 3 ml to 1 mL, the viscosity of the injection solution can rise thereby hampering the ease of administration of the injection. It is therefore important to make judicious use of co-solvents/solubilisers, along with water to formulate injection solutions of water-soluble salts of diclofenac, to provide 75 mg to 100 mg in about 1 mL without substantially increasing the viscosity. Further it is also desirable to provide injectable preparations with low content of co-solvents/solubilisers to minimize their side effects.